高下 純平

BACKGROUND: The effect of renal function on long-term dual antiplatelet therapy using cilostazol for secondary stroke prevention is unknown. We investigated the effect of estimated glomerular filtration rate (eGFR) on the efficacy and safety of long-term dual antiplatelet therapy involving cilostazol. METHODS: We performed a post hoc analysis of a multicenter, open-label, randomized controlled trial of patients with high-risk non-cardioembolic ischemic stroke who were randomly assigned to take aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel and followed for 0.5-3.5 years. Patients were divided into three groups according to their baseline eGFR [normal or increased eGFR (≥90); mildly decreased eGFR (60-89); moderately decreased eGFR (<60 mL/min/1.73m2)]. RESULTS: A total of 1749 patients with complete eGFR data were included. The recurrence of ischemic stroke was less common with dual therapy than with monotherapy in patients with mildly decreased eGFR (adjusted HR, 0.35; 95 % CI, 0.19-0.66), but there was no difference between dual therapy and monotherapy in patients with moderately decreased eGFR (0.78; 0.34-1.82) or in those with normal or increased eGFR (0.48; 0.14-1.64). CONCLUSIONS: Long-term dual antiplatelet therapy with cilostazol was more efficacious in decreasing recurrent ischemic stroke than monotherapy for patients with mildly decreased eGFR, but not for those with moderately decreased eGFR or those with normal or increased eGFR. Trial Registration Information: ClinicalTrials.govNCT01995370.

BACKGROUND: Insertable cardiac monitoring (ICM) detects atrial fibrillation (AF) in substantial proportions of cryptogenic stroke, noncryptogenic ischemic stroke without known AF, and nonstroke patients who are at risk of underlying AF. Given differences in patient characteristics across studies, there may be differences in AF detection rates on ICM across these subgroups that have not been identified. We investigate whether AF detection rates on ICM are higher in cryptogenic stroke or transient ischemic attack (C-IS/TIA) patients compared with individuals with noncryptogenic stroke or without stroke, when accounting for differences in study populations. METHODS: This is an individual-participant data meta-analysis of prospective studies and randomized controlled trials of ICM in C-IS/TIA, noncryptogenic ischemic stroke, and nonstroke patients. Multilevel multivariable logistic regression models were used to test whether C-IS/TIA is associated with increased AF detection relative to other categories. We performed multiple imputation to derive values for variables with <20% missing data and used Rubin's rules to estimate adjusted odds ratios by combining 100 postimputation data sets. The primary outcome was detection of AF. The attributable risk was derived by application of Bayes' Theorem. RESULTS: Two randomized controlled trials and 12 prospective studies were included with a total of 1562 C-IS/TIA patients and 474 non-C-IS/TIA patients. In adjusted multilevel logistic regression analyses, AF detection was higher in C-IS/TIA patients (adjusted odds ratio, 1.90 [95% CI, 1.18-3.06]; P=0.009), indicating that 47% of AF detected in C-IS/TIA is pathogenic. Limiting the comparator group to ischemic stroke or history of stroke yielded similar results (adjusted odds ratio, 2.83 [95% CI, 1.47-5.44]; P=0.002). Days to AF detection were significantly shorter in C-IS/TIA patients (median 65 versus 169; P<0.001). CONCLUSIONS: In this individual-participant data meta-analysis of patients undergoing ICM, AF detection was higher in C-IS/TIA patients, with shorter time to AF detection compared with noncryptogenic/nonstroke individuals. These findings suggest that some of the AF detected in patients with C-IS/TIA may be pathogenic.

BACKGROUND AND OBJECTIVES: We aimed to clarify the association between neurological deterioration pre-endovascular therapy (EVT) and outcome in patients with large-vessel occlusion due to intracranial atherosclerotic disease (ICAD-LVO) undergoing EVT. METHODS: Consecutive patients with acute ischemic stroke due to ICAD-LVO within 24 h of onset who underwent EVT were enrolled in the Japanese multicenter registry from 2017 to 2019. Patients were grouped according to neurological severity transition as follows: mild symptoms (baseline National Institutes of Health Stroke Scale [NIHSS] score <6 and NIHSS score pre-EVT <6), symptom deterioration (baseline NIHSS score <6 and NIHSS score pre-EVT ≥6), and severe symptoms (baseline NIHSS score ≥6 and NIHSS score pre-EVT ≥6). Outcomes included favorable outcomes (modified Rankin Scale [mRS] score of 0-2 at 90 days), ordinal mRS shift, and symptomatic intracranial hemorrhage. Multivariable logistic regression assessed the association of outcomes with the transition of neurological severity by calculating odds ratios and 95% CIs, with mild symptoms as reference. RESULTS: In total, 480 patients with acute ICAD-LVO who underwent EVT (150 women [31.2%]; median age, 72 years IQR, 66-80) and had median baseline NIHSS score 12 (IQR, 6-20) were analyzed. Patients with symptom deterioration (n = 34) and severe symptoms (n = 375) had lower favorable outcomes (deterioration 38.2% vs mild 62.9%; adjusted odds ratio 0.30, 95% CI 0.09-0.97, severe 35.3%; 0.47, 0.33-0.65) and a significant mRS shift (deterioration vs mild; 3.63, 1.46-9.03, severe; 2.27, 1.74-2.96) than those with mild symptoms (n = 71). Symptomatic intracranial hemorrhage rates did not differ (mild 0%; deterioration 0%; severe 1.9%). CONCLUSION: Patients with ICAD-LVO who experienced worsening symptoms were less likely to achieve favorable outcomes after EVT than those with mild symptoms. Early identification of neurological deterioration and EVT intervention may improve outcomes in these patients.

PURPOSE: The Woven EndoBridge (WEB) was introduced in Japan in January 2021 and approved for all subtypes of wide-neck bifurcation aneurysms (WNBA). This retrospective study evaluated the safety and efficacy of the WEB device for all subtypes of WNBA. MATERIALS AND METHODS: All patients treated with the WEB at our facility between January 2021 and May 2024 was reviewed. We selected the WEB device according to an oversizing policy, based on cumulative clinical evidence from global experience. RESULTS: We analyzed 120 aneurysms in 117 patients (56 males and 61 females with a mean age of 65.5±12.7 years). There were 45 anterior communicating artery aneurysms, 27 middle cerebral artery aneurysms, 17 internal carotid artery-posterior communicating artery aneurysms, 15 basilar artery top aneurysms, and 16 aneurysms in other locations. Aneurysm characteristics included a maximum diameter of 6.5 [5.3, 7.7] mm, height of 4.9 [3.9, 6.0] mm, width of 4.8 [4.0, 6.2] mm, and dome/neck ratio of 1.2 [1.1, 1.4]. All data are expressed in median [interquartile range]. Angiographic follow-up at 12 months in 96 cases showed complete obliteration in 68.8% and adequate obliteration in 90.6% of cases. Intraoperative ischemic events occurred in 5 cases (4.2%). Hemorrhagic events occurred in 2 cases (1.7%), with symptoms resolving by discharge, except for 1 case of mild paralysis. During follow-up, 1 patient developed a major stroke, resulting in morbidity (0.8%). Retreatment was required in 3 cases (2.5%). On multivariate analysis for complete occlusion at 12 months following WEB treatment, age was statistically associated with the outcome (odds ratio, 0.957 per year; 95% confidence interval, 0.919-0.996; P=0.033). CONCLUSION: WEB is safe and effective for all subtypes of WNBA, with a low retreatment rate using an oversizing policy. This is the first report in a Japanese population.

PURPOSE: Digital subtraction angiography (DSA) is the gold standard for follow-up evaluation of intracranial aneurysms treated with the Woven EndoBridge (WEB) device. This study aimed to assess the efficacy of high-resolution CT angiography (HR-CTA) as a less invasive alternative by comparing its diagnostic performance with that of DSA. METHODS: This single-center retrospective study analyzed the angiographic and clinical data of patients treated with the WEB device for cerebral aneurysms between January 2021 and December 2024. Patients who underwent HR-CTA within 2 weeks before or after follow-up DSA were included. Occlusion status was assessed using the Bicêtre Occlusion Scale Score (BOSS) and binary classification. The concordance rate between HR-CTA and DSA was evaluated. RESULTS: A total of 54 eligible examinations were identified. Using the BOSS, 46 examinations were concordant, resulting in an agreement rate of 85.2%. The Cohen's κ coefficient was 0.81 (95% CI 0.69 to 0.93), indicating a very high level of agreement. All discordant cases resulted from HR-CTA overestimating occlusion status; however, HR-CTA accurately identified aneurysm remnants. Univariate analyses identified BOSS 0' as the only significant factor contributing to discrepancies. In the binary evaluation, all 54 examinations were fully concordant (κ=1.00, 95% CI 1.00 to 1.00). CONCLUSIONS: HR-CTA demonstrated a high concordance rate with DSA for evaluating occlusion status after WEB placement. Its reliable assessment of aneurysm remnants suggests HR-CTA could serve as a practical and less invasive alternative to DSA in follow-up evaluations.

PURPOSE: We aimed to clarify the clinical characteristics and outcomes of patients with in-hospital onset ischemic stroke (IOS) compared with those in patients with community-onset ischemic stroke (COS). METHODS: Patients from the Japan Stroke Data Bank, a hospital-based multicenter prospective registry, who were diagnosed with acute ischemic stroke (AIS) within 24 h of onset between January 2001 and December 2020 were included in this study. We assessed favorable outcomes at discharge corresponding to a modified Rankin Scale (mRS) score of 0-2, unfavorable outcomes corresponding to an mRS score of 5-6, and mortality. We also examined trends in these outcomes at 4-year intervals over a period of 20 years. RESULTS: Of the 100,865 patients analyzed, 2979 had IOS (1416 women, mean age 77 ± 12 years) and were older than those with COS (n = 97,886; 39,110 women, mean age 74 ± 12 years). Multivariate analysis revealed that younger age, higher premorbid mRS score, absence of stroke history, normotension, congestive heart failure, coronary artery disease, chronic kidney disease, liver disease, malignancy, tendency to bleed, and cardioembolic stroke were positively associated with IOS. Compared with COS, IOS was inversely associated with a favorable outcome (42.1% vs 64.8%, adjusted odds ratio [aOR] 0.72 [95% confidence interval (CI) 0.63-0.82]), positively associated with an unfavorable outcome (mRS 5-6 at discharge; 34.3% vs 15.5%, aOR 1.31 [95% CI 1.16-1.48]), and mortality (11.8% vs 4.6%, aOR 1.59 [95% CI 1.37-1.84]). Over 20 years, the mortality rate significantly decreased in both patients with IOS and COS (p < 0.01 both). CONCLUSION: IOS is associated with unfavorable outcomes and higher mortality rates during acute hospitalization. The mortality rates in patients with IOS decreased over time, similar to those observed in patients with COS.

PURPOSE: Visualizing the culprit perforating artery in subcortical infarction using in vivo imaging is challenging. We aimed to identify the culprit perforating arteries in subcortical infarctions and assess their morphology using an image fusion technique. METHODS: We retrospectively reviewed consecutive patients who had an ischemic stroke in the anterior circulation perforating area (caudate nucleus, lentiform nucleus, internal capsule, corona radiata, or centrum semiovale) and underwent three-dimensional rotational-angiography (3D-RA) and 3D fluid-attenuated inversion recovery MRI. Images were registered using an original fusion software. The spatial relationship between the infarction and culprit perforating artery and its morphological characteristics were analyzed in the fusion images. Stenosis was defined as > 50% luminal narrowing or a focal intraluminal defect in the perforating artery. RESULTS: Of 118 patients, the culprit perforating artery was identified in 52 patients (44%); They tended to have younger age and had a higher baseline NIHSS score and higher prevalence of infarcts in the lentiform nucleus than did those without identified culprit perforating artery. Among the 44 patients with assessable morphology of the culprit perforating artery, 27 (61%) exhibited stenosis in the proximal segment. Atrial fibrillation was more frequent in patients without stenosis in the proximal segment of the culprit perforating artery than in those with stenosis (29% vs. 4%, P = 0.03). CONCLUSION: The 3D-RA and MRI fusion technique enables identification of the culprit perforating arteries in subcortical infarctions, especially in the lentiform nucleus. Morphological features of the culprit perforating artery may be associated with the etiological mechanism of stroke.

BACKGROUND: This study aimed to determine the efficacy of flow diverters (FDs) for small/medium (≤10 mm) aneurysms and analyzed the factors that prevent aneurysm occlusion. METHODS: This retrospective single-center study evaluated the angiographic and clinical data of consecutive patients between June 2020 and February 2023. RESULTS: Overall, 121 small/medium aneurysms were observed in 106 patients treated with FDs. The median dome diameter was 6.1 (5.1-7.2) mm. Symptomatic thromboembolic complications were observed in four (3.7 %) patients, and none showed a major ischemic stroke. Intracranial hemorrhage was detected using postprocedural computed tomography in one (0.9 %) patient with asymptomatic subarachnoid hemorrhage. The rate of permanent neurological deficits was 1.8 %, and the mortality rate was 0 %. No delayed ischemic or hemorrhagic complications were observed during follow-up. Angiographic follow-up revealed complete and adequate occlusion (O'Kelly-Marotta grades C and D) rates of 77.5 % and 90.8 %, respectively. On multivariate analysis, incomplete occlusion was only associated with the presence of a branch vessel from the aneurysm dome (P < 0.01). In aneurysms with incorporated branch vessels, univariate analysis revealed that coil usage was a predictor of complete occlusion (P = 0.03). Moreover, even without using coils, effective occlusion was achieved when the branch vessel diameter was small (P = 0.03). CONCLUSIONS: FDs are an effective and safe treatment option for small/medium aneurysms. The presence of incorporated branch vessels can predict incomplete occlusion. Even in aneurysms with incorporated branch vessels, FD can obtain therapeutic effects by adding coil embolization or treating with only FD if the branch vessel diameter is small.

We report a case in which a novel distal access catheter proved successful in the placement of a flow diverter for a challenging distal cerebral artery lesion. We discuss the advantages and pitfalls of this technique and considerations for its use. A 74-year-old female presented with intermittent headaches, and was diagnosed with a dissecting aneurysm at the proximal right posterior cerebral artery with a sharp bleb, measuring 9.8 mm in diameter. Given the complex vascular anatomy, stent-assisted coil embolization was initially considered but deemed high risk for dual catheter for jailing technique with 6-Fr size guiding catheter due to the tortuosity and stenosis of the parent vessel. Therefore, we opted for flow diverter treatment, which presented its challenges during delivery. By employing a low-profile distal access catheter, Phenom Plus (outer diameter: 4.2-Fr. inner diameter: 1.13 mm; Medtronic, Minneapolis, Minnesota, United States), with a minimal ledge between it and the delivery catheter, Phenom 27 (outer diameter: 2.8-Fr, 0.91 mm; Medtronic), we successfully crossed the neck of the aneurysm with Phenom Plus and placed the flow diverter. While acknowledging potential risks, this case demonstrates the value of the neck-crossing technique using a low-profile distal access catheter as an alternative option for treating challenging peripheral artery aneurysms with flow diverters. This technique offers promise in specific situations where conventional methods pose challenges.

PURPOSE: The safety and efficacy of Woven EndoBridge (WEB) treatment has been proven. However, only a few standard techniques for safe and versatile WEB deployment have been described in the literature. In this study, we introduce the "make a flower bud and push at neck" technique to achieve safety and versatility during WEB treatment, referred to simply as the "flower bud" technique. METHODS: Consecutive patients who underwent WEB treatment between January 2021 and October 2023 were included. We dichotomized the techniques of WEB deployment into two: the "flower bud" technique and the ordinary unsheath technique. Patient demographics, clinical characteristics of the aneurysms, and treatment results were compared between the two techniques to evaluate the safety and versatility of the "flower bud" technique. RESULTS: Of 100 aneurysms, 96 were eligible in the study. The "flower bud" technique was applied in 79 aneurysms (82.3 %), and the ordinary unsheath technique was applied in 17 aneurysms (17.7 %). The aneurysm location significantly differed between both techniques. The degree of parent artery-aneurysm (PA) angle and the proportion of the PA angle ≥ 45° were significantly higher in the "flower bud" technique than in the ordinary unsheath technique (P = 0.024 and P = 0.009, respectively). Effective angiographical results and low morbidity/mortality rate were similar in the techniques, although intraoperative rupture was experienced in one aneurysm treated using the ordinary unsheath technique. CONCLUSION: The "make a flower bud and push at neck" technique could be safer and more versatile in treating cerebral aneurysms by WEB compared to the ordinary unsheath technique.

OBJECTIVE: The Woven EndoBridge (WEB; MicroVention TERUMO, Tustin, CA, USA) is an intrasaccular flow disruptor developed for the treatment of wide-neck bifurcation aneurysms (WNBA). While its safety and satisfactory mid- to long-term treatment outcomes have been documented, there have also been reports of complications such as WEB protrusion and migration. We encountered 3 cases in which the WEB protruded or migrated to the parent vessel after deployment, necessitating retrieval. In this report, we address the technical tips for retrieval techniques and factors associated with these complications, including a literature review. CASE PRESENTATION: Of the 120 cases of our experience with WEB treatment for cerebral aneurysms for the period since January 2021, 3 required WEB retrievals. In 2 cases, significant WEB migration toward the parent vessel occurred while maneuvering the delivery microcatheter because of sticky detachment. In the remaining case, after detachment of the WEB, tilting occurred, leading to a strong protrusion into one of the branches, which prevented guiding the microcatheter for bailout stenting. In all cases, the proximal marker of the WEB was captured using an Amplatz Goose Neck Microsnare (Medtronic, Minneapolis, MN, USA) pulled back into the VIA catheter (the delivery catheter for the WEB; MicroVention TERUMO), and further into an intermediate catheter positioned as close to the aneurysm as possible, enabling uneventful retrieval. CONCLUSION: None of the cases damaged the aneurysm or proximal parent vessel wall, and additional aneurysm occlusion treatment was performed. However, WEB protrusions and migration are rare. When retrieval is required, it is crucial to act swiftly owing to the risk of distal thrombosis from the lumen inside of the WEB. Therefore, recognizing Goose Neck Microsnare as a retrieval technique is valuable.

As endovascular therapy for ischemic stroke has advanced, we are getting increasing opportunities to study cerebral thromboemboli histologically. These opportunities have not been fully exploited, but some reports suggest that thromboemboli retrieved from cancer patients with stroke are platelet-richer than those from non-cancer patients. Nonbacterial thrombotic endocarditis (NBTE) is an important cause of ischemic stroke in cancer patients. In this study, we analyzed 20 autopsy cases of NBTE (13 of which had advanced cancer), along with cases of cerebral embolism associated with atrial fibrillation (AF, n = 11) and infective endocarditis (IE, n = 7). The histological features of NBTE vegetations (n = 20) were fairly consistent among cases: they were overwhelmingly platelet-dominant and spatially homogeneous, containing few erythrocytes or inflammatory cells. They were little organized, if at all, and were not associated with valvular destruction. Cerebral emboli associated with NBTE (n = 7) were also platelet-dominant. Intracardiac thrombi/vegetations and cerebral emboli associated with AF and IE, in contrast, contained variable amounts of platelets and erythrocytes. NBTE vegetations/emboli, compared with AF thrombi/emboli, had significantly higher %platelet area (intracardiac vegetations/thrombi: 70 ± 15 % vs 33 ± 20 %, p < 0.001; cerebral emboli: 65 ± 16 % vs 25 ± 22 %, p < 0.001) and lower %erythrocyte area (vegetations/thrombi: 9 ± 7 % vs 61 ± 21 %, p < 0.001; emboli: 20 ± 11 % vs 70 ± 9 %, p < 0.001). These results suggest that some platelet-rich thrombi retrieved during mechanical thrombectomy for ischemic stroke in cancer patients are likely to have originated from NBTE. Clinical diagnosis of NBTE is often difficult, but histological analysis of retrieved thrombi may help identify this underdiagnosed condition.

BACKGROUND: Although endovascular therapy (EVT) is effective for large ischemic region strokes, the impact of hyperglycemia remains unclear. METHODS AND RESULTS: We analyzed data from the RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Large Ischemic Core) trial, which randomized stroke patients with Alberta Stroke Program Early Computed Tomography Score of 3 to 5 to EVT versus medical management. Outcomes were compared among patients with normoglycemia (<140 mg/dL), moderate hyperglycemia (≥140, <180 mg/dL), and severe hyperglycemia (≥180 mg/dL) on admission. Among 200 patients (median age 76.5 years, median glucose level 131 mg/dL, EVT 50%), diabetes prevalence was 10.0%, 18.4%, and 71.0% in the groups with normoglycemia (n=120), moderate hyperglycemia (n=49), and severe hyperglycemia (n=31), respectively. Achievement of modified Rankin Scale score 0 to 3 at 90 days was less frequent in the group with severe hyperglycemia (6.5%) than in the groups with normoglycemia (25.0%) and moderate hyperglycemia (24.5%), with adjusted odds ratios (aOR) of 1.48 (95% CI, 0.59-3.72) for moderate and 0.17 (95% CI, 0.03-0.95) for severe hyperglycemia relative to normoglycemia. The risk of symptomatic intracranial hemorrhage was higher for moderate hyperglycemia (6.1%; aOR, 2.86 [95% CI, 0.42-19.71]) and particularly for severe hyperglycemia (25.8%; aOR, 18.59 [95% CI, 2.47-139.87]) compared with normoglycemia (2.5%). Symptomatic intracranial hemorrhage rates were similar for EVT and medical management in normoglycemia (1.6% versus 3.4%) and moderate hyperglycemia (5.0% versus 6.9%), but for severe hyperglycemia, the rate was higher in patients with EVT (36.8%) than in those without (8.3%). CONCLUSIONS: Severe hyperglycemia was associated with worse functional prognosis and increased symptomatic intracranial hemorrhage in large ischemic region strokes. REGISTRATION: URL: https://clinicaltrials.gov. Identifier: NCT03702413.

BACKGROUND AND AIM: Some patients with intracerebral hemorrhage are on antithrombotic agents at the time of the event and these may worsen outcome, but the relative risk of different oral anticoagulants and antiplatelet agents is uncertain. We determined associations between pre-onset intake of antithrombotic agents and initial stroke severity, and outcomes, in patients with intracerebral hemorrhage. METHODS: Patients with intracerebral hemorrhage admitted within 24 hours after onset between January 2017 and December 2020 and recruited to the Japan Stroke Data Bank, a hospital-based multicenter prospective registry, were included. Enrolled patients were classified into four groups based on the type of antithrombotic agents being used on admission. The outcomes were the National Institutes of Health Stroke Scale (NIHSS) score on admission and modified Rankin Scale (mRS) of 5-6 at discharge. RESULTS: Of a total 9,810 patients with intracerebral hemorrhage (4,267 females; mean age, 70±15 years), 77.1% were classified into the no-antithrombotic group, 13.2% into the antiplatelet group, 4.0% into the warfarin group, and 5.8% into the direct oral anticoagulant (DOAC) group. Median (interquartile range) NIHSS score on admission was 12 (5-22), 13 (5-26), 15 (5-30), and 13 (6-24), respectively, in the four groups. In multivariable analysis, the pre stroke warfarin use was associated with higher NIHSS score (adjusted incidence rate ratio, 1.09 [95%confidence interval (CI), 1.06-1.13], with the no-antithrombotic group as the reference), but the antiplatelet group (1.00 [95%CI, 0.98-1.02]) and DOAC group (0.98 [95%CI, 0.95-1.01]) was not. The rate of mRS 5-6 at discharge was 30.8%, 41.9%, 48.6%, and 41.5%, respectively, in the four groups. In multivariable analysis, pre stroke warfarin use was associated with mRS 5-6 (adjusted odds ratio: 1.90 [95%CI, 1.28-2.81], with the no-antithrombotic group as the reference), but the antiplatelet group (1.12 [95%CI, 0.91-1.37]) and DOAC group (1.25 [95%CI, 0.88-1.77]) was not. CONCLUSIONS: Patients who were taking warfarin prior to intracerebral hemorrhage onset suffered more severe intracerebral hemorrhage as evidenced by higher admission NIHSS and higher discharge mRS. In contrast, no increase in severity was seen with antiplatelet agents.

AIM: Severity, functional outcomes, and their secular changes in acute atrial fibrillation (AF)-associated stroke patients were determined. METHODS: Acute ischemic stroke patients with AF in a hospital-based, multicenter, prospective registry from January-2000 through December-2020, were compared with those without AF. The co-primary outcomes were the initial severity assessed by the NIH Stroke Scale (NIHSS) score and favorable outcome assessed by the modified Rankin Scale scores 0-2 at hospital discharge. RESULTS: Of the 142,351 patients studied, 33,870 had AF. AF patients had higher NIHSS scores (median 9 vs. 3, adjusted coefficient 5.468, 95% CI 5.354-5.582) than non-AF patients. Favorable outcome was less common in AF patients than in non-AF patients in the unadjusted analysis (48.4% vs. 70.4%), but it was more common with adjustment for the NIHSS score and other factors (adjusted OR 1.110, 95% CI 1.061-1.161). In AF patients, the NIHSS score decreased throughout the 21-year period (adjusted coefficient -0.088, 95% CI -0.115 - -0.061 per year), and the reduction was steeper than in non-AF patients (P＜0.001). In AF patients, favorable outcome became more common over the period (adjusted OR 1.018, 95% CI 1.010-1.026), and the increase was steeper than in non-AF patients (P＜0.001); the increase was no longer significant after further adjustment by reperfusion therapy. CONCLUSIONS: Initial stroke severity became milder and functional outcomes improved in AF patients over the 21-year period. These secular changes were steeper than in non-AF patients, suggesting that AF-associated stroke seemed to reap more benefit of recent development of stroke care than stroke without AF.

BACKGROUND AND AIM: To investigate the prognostic implication of body mass index (BMI) on clinical outcomes after acute ischemic and hemorrhagic stroke. METHODS: The subjects of the study included adult patients with available baseline body weight and height data who had suffered an acute stroke and were registered in the Japan Stroke Data Bank-a hospital-based, multicenter stroke registration database-between January 2006 and December 2020. The outcome measures included unfavorable outcomes defined as a modified Rankin Scale (mRS) score of 5-6 and favorable outcomes (mRS 0-2) at discharge, and in-hospital mortality. Mixed effects logistic regression analysis was conducted to determine the relationship between BMI categories (underweight, normal weight, overweight, class I obesity, class II obesity; <18.5, 18.5-23.0, 23.0-25.0, 25-30, ⩾30 kg/m2) and the outcomes, after adjustment for covariates. RESULTS: A total of 56,230 patients were assigned to one of the following groups: ischemic stroke (IS, n = 43,668), intracerebral hemorrhage (ICH, n = 9741), and subarachnoid hemorrhage (SAH, n = 2821). In the IS group, being underweight was associated with an increased likelihood of unfavorable outcomes (odds ratio, 1.47 (95% confidence interval (CI):1.31-1.65)) and in-hospital mortality (1.55 (1.31-1.83)) compared to outcomes in those with normal weight. Being overweight was associated with an increased likelihood of favorable outcomes (1.09 (1.01-1.18)). Similar associations were observed between underweight and these outcomes in specific IS subtypes (cardioembolic stroke, large artery stroke, and small-vessel occlusion). Patients with a BMI ⩾30.0 kg/m2 was associated with an increased likelihood of unfavorable outcomes (1.44 (1.01-2.17)) and in-hospital mortality (2.42 (1.26-4.65)) in large artery stroke. In patients with ICH, but not those with SAH, being underweight was associated with an increased likelihood of unfavorable outcomes (1.41 (1.01-1.99)). CONCLUSIONS: BMI substantially impacts functional outcomes following IS and ICH. Lower BMI consistently affected post-stroke disability and mortality, while higher BMI values similarly affected these outcomes after large artery stroke.

BACKGROUND: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM). METHODS: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS2 score. RESULTS: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P<0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively. CONCLUSIONS: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

BACKGROUND: Atrial fibrillation (AF) is known to be a strong risk factor for stroke. However, the risk of stroke recurrence in patients with cryptogenic stroke with AF detected after stroke by an insertable cardiac monitor (ICM) is not well known. We sought to evaluate the risk of ischemic stroke recurrence in patients with cryptogenic stroke with and without ICM-detected AF. METHODS AND RESULTS: We retrospectively reviewed patients with cryptogenic stroke who underwent ICM implantation at 8 stroke centers in Japan. Cox regression models were developed using landmark analysis and time-dependent analysis. We set the target sample size at 300 patients based on our estimate of the annualized incidence of ischemic stroke recurrence to be 3% in patients without AF detection and 9% in patients with AF detection. Of the 370 patients, 121 were found to have AF, and 110 received anticoagulation therapy after AF detection. The incidence of ischemic stroke recurrence was 4.0% in 249 patients without AF detection and 5.8% in 121 patients with AF detection (P=0.45). In a landmark analysis, the risk of ischemic stroke recurrence was not higher in patients with AF detected ≤90 days than in those without (hazard ratio, 1.47 [95% CI, 0.41-5.28]). In a time-dependent analysis, the risk of ischemic stroke recurrence did not increase after AF detection (hazard ratio, 1.77 [95% CI, 0.70-4.47]). CONCLUSIONS: The risk of ischemic stroke recurrence in patients with cryptogenic stroke with ICM-detected AF, 90% of whom were subsequently anticoagulated, was not higher than in those without ICM-detected AF.

BACKGROUND AND OBJECTIVE: The association between focal vs nonfocal presenting symptom and diffusion-weighted imaging (DWI) positivity in relation to onset-to-imaging time in patients with transient neurologic events remains unclear. We hypothesize that episodes consisting of focal symptoms would have proportionally higher DWI-positive imaging at later onset-to-imaging times. METHODS: Patients with transient neurologic symptoms and a normal neurologic examination who had DWI in the combined data set of 3 cohort studies were included. We used logistic regression models to evaluate the association between each type of presenting symptom (motor weakness, speech impairment, sensory symptoms, vision loss, diplopia, gait instability, dizziness, headache, presyncope, and amnesia) and DWI positivity after adjusting for clinical variables (age, sex, history of stroke, dyslipidemia, coronary artery disease, atrial fibrillation, symptoms duration [<10, 10-59, ≥60 minutes, or unclear], and study source). We stratified the results by onset-to-imaging time categories (<6 hours, 6-23 hours, and ≥24 hours). RESULTS: Of the total 2,411 patients (1,345 male, median age 68 years), DWI-positive lesions were detected in 598 patients (24.8%). The prevalence of DWI positivity was highest in those with motor weakness (34.7%), followed by speech impairment (33.5%). In a multivariable analysis, the presence of motor weakness, speech impairment, and sensory symptoms was associated with DWI positivity, while vision loss and headache were associated with lower odds of DWI positivity, but nevertheless had 13.6% and 15.3% frequency of DWI positive. The odds of being DWI positive varied by onset-to-imaging time categories for motor weakness, with greater odds of being DWI positive at later imaging time (<6 hours: odds ratio [OR] 1.25, 95% confidence interval [CI] 0.84-1.87; 6-23 hours: OR 2.24, 95% CI 1.47-3.42; and ≥24 hours: OR 2.42, 95% CI 1.74-3.36; interaction p = 0.033). Associations of other symptoms with DWI positivity did not vary significantly by time categories. DISCUSSION: We found that onset-to-imaging time influences the relationship between motor weakness and DWI positivity in patients with transient neurologic events. Compared with motor, speech, and sensory symptoms, visual or nonfocal symptoms carry a lower but still a substantive association with DWI positivity.

OBJECTIVE: LEONIS Mova (SB-KAWASUMI LABORATORIES, Kanagawa, Japan, hereinafter called LEONIS Mova) is a steerable microcatheter (MC) that enables angle adjustment of the catheter tip using a hand-operated dial. LEONIS Mova may be useful for flow diverter placement when access to the distal parent artery with a conventional MC and microguidewire (MGW) is considered difficult or impossible. Here, we report three such cases encountered during flow diverter placement in large and giant internal carotid artery aneurysms. CASE PRESENTATION: In Case 1, a strong S-shaped curve was observed in the proximal parent artery of a giant cerebral aneurysm, and the luminal structure of the parent artery was lost within the aneurysm. It was anticipated that the distal side of the parent artery would be difficult to access with conventional MC and MGW. By adjusting the tip of the LEONIS Mova toward the aneurysm outlet beyond the S-shaped curve, it was possible to induce the MGW to secure the distal parent artery easily. In Case 2, the inflow and outflow axes of the parent artery were completely misaligned at the site of the aneurysm, and stenosis was present in the distal parent artery. Firmly bending the catheter tip increased accommodation for the catheter, enabling the induction of an MGW to access the distal parent artery without kicking back. In Case 3, the lesion extended from the cavernous portion to the petrosal portion; however, by adjusting the tip of the LEONIS Mova toward the aneurysm outlet, it was possible to induce the MGW to secure the distal parent artery easily. In each case, the LEONIS Mova enabled more secure and prompt access to the parent artery than anticipated and facilitated flow diverter placement. CONCLUSION: Encountering difficult-to-access lesions is one reason endovascular treatment may be unsuccessful. The LEONIS Mova is an excellent device that can overcome this obstacle, and its utility in certain applications should be recognized.

High B-type natriuretic peptide (BNP) levels are associated with new atrial fibrillation (AF). This study investigated the distribution of AF detection rates according to BNP levels in patients with cryptogenic stroke (CS) using an insertable cardiac monitor (ICM). We enrolled consecutive patients with CS who underwent ICM implantation between October 2016 and September 2020 at eight stroke centers in Japan. Those with BNP levels were divided into three groups by tertiles. We evaluated the association of BNP levels with AF detection. Youden's index was calculated to identify the optimal cutoff for BNP. Of 417 patients, we analyzed 266 patients with BNP data. The tertile range of BNP level was 19.0 to 48.5 pg/mL. AF detection rate was 13.3%/year, 12.8%/year, and 53.7%/year in the low-BNP (≤19.0), mid-BNP (19.1-48.4), and high-BNP (≥48.5) groups, respectively (log-rank trend p < 0.01). Compared with low-BNP group, the adjusted hazard ratios for AF detection in mid-and high-BNP groups were 0.91 [95% confidence interval (CI) 0.46-1.78] and 2.17 (95% CI 1.14-4.13), respectively. Receiver operating characteristic curve analysis showed the optimal cutoff value was 43.4 pg/mL. The area under curve using BNP to predict AF detection was 0.69. The BNP level was associated with AF detection in patients with CS. This relationship changed around the BNP levels of 40-50 pg/mL.

AIM: The nationwide verification of intravenous thrombolysis (IVT) was rarely performed after the extension of the therapeutic time window of alteplase or after the expansion of mechanical thrombectomy (MT). We aimed to examine the long-term change in accurate real-world outcomes of IVT in patients with acute ischemic stroke (AIS) using the Japan Stroke Databank, a representative Japan-wide stroke database. METHODS: We extracted all patients with AIS who received IVT with alteplase between October 11, 2005, the approval date for alteplase use for AIS in Japan, and December 31, 2020. Patients were categorized into three groups using two critical dates in Japan as cutoffs: the official extension date of the therapeutic time window for IVT to within 4.5 h of symptom onset and the publication date of the revised guideline, where the evidence level of MT was heightened. We assessed the yearly trend of IVT implementation rates and the secular changes and three-group changes in clinical outcomes at discharge. RESULTS: Of 124,382 patients with AIS, 9,569 (7.7%) received IVT (females, 41%; median age, 75 years). The IVT implementation rate has generally increased over time and plateaued in recent years. The proportion of favorable outcomes (modified Rankin Scale score of 0-2) increased yearly over 15 years. The results of the changes in the outcomes of the three groups were similar to those of the annual changes. CONCLUSIONS: We revealed that IVT implementation rates in patients with AIS increased, and the functional outcome in these patients improved over 15 years. Therefore, the Japanese IVT dissemination strategy is considered appropriate and effective.

BACKGROUND: An insertable cardiac monitor (ICM) and transesophageal echocardiography (TEE) are useful for investigating potential embolic sources in cryptogenic stroke, of which atrial fibrillation (AF) is a critical risk factor for stroke recurrence. The association of left atrial appendage flow velocity (LAA-FV) on TEE with ICM-detected AF is yet to be elucidated. METHODS: CRYPTON-ICM (CRYPTOgenic stroke evaluation in Nippon using ICM) is a multicenter registry of cryptogenic stroke with ICM implantation, and patients whose LAA-FV was evaluated on TEE were enrolled. The primary outcome was the detection of AF (> 2 min) on ICM. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cut-off of LAA-FV, and factors associated with ICM-detected AF were assessed. RESULTS: A total of 307 patients (age 66.6 ± 12.3 years; 199 males) with median follow-up of 440 (interquartile range 169-726) days were enrolled; AF was detected in 101 patients. The lower-tertile LAA-FV group had older age, more history of congestive heart failure, and higher levels of B-type natriuretic peptide (BNP) or N-terminal proBNP (all P < 0.05). On ROC analysis, LAA-FV < 37.5 cm/s predicted ICM-detected AF with sensitivity of 26.7% and specificity of 92.2%. After adjustment for covariates, the lower tertile of LAA-FV (hazard ratio [HR], 1.753 [1.017-3.021], P = 0.043) and LAA-FV < 37.5 cm/s (HR 1.987 [1.240-3.184], P = 0.004) predicted ICM-detected AF. CONCLUSIONS: LAA-FV < 37.5 cm/s predicts AF. TEE is useful not only to evaluate potential embolic sources, but also for long-term detection of AF on ICM by measuring LAA-FV in cryptogenic stroke. http://www.umin.ac.jp/ctr/ (UMIN000044366).

BACKGROUND: Clinical outcomes of unknown onset stroke (UOS) are influenced by the enlargement of the therapeutic time window for reperfusion therapy. This study aimed to investigate and describe the characteristics and clinical outcomes of patients with UOS. METHODS: Patients with acute ischemic stroke (AIS) who were admitted within 24 h of their last known well time, from January 2017 to December 2020, were included. Data were obtained from a long-lasting nationwide hospital-based multicenter prospective registry: the Japan Stroke Data Bank. The co-primary outcomes were the National Institutes of Stroke Scale (NIHSS) scores on admission and unfavorable outcomes at discharge, corresponding to modified Rankin Scale (mRS) scores of 3-6. RESULTS: Overall, 26,976 patients with AIS were investigated. Patients with UOS (N = 5783, 78 ± 12 years of age) were older than patients with known onset stroke (KOS) (N = 21,193, 75 ± 13 years of age). Age, female sex, higher premorbid mRS scores, atrial fibrillation, and congestive heart failure were associated with UOS in multivariate analysis. UOS was associated with higher NIHSS scores (median = 8 [interquartile range [IQR]: 3-19] vs. 4 [1-10], adjusted incidence rate ratio = 1.37 [95% CI: 1.35-1.38]) and unfavorable outcomes (52.1 vs. 33.6%, adjusted odds ratio = 1.27 [1.14-1.40]). Intergroup differences in unfavorable outcomes were attenuated among females (1.12 [0.95-1.32] vs. males 1.38 [1.21-1.56], P = 0.040) and in the subgroup that received reperfusion therapy (1.10 [0.92-1.33] vs. those who did not receive therapy 1.23 [1.08-1.39], P = 0.012). CONCLUSIONS: UOS was associated with unfavorable outcomes but to a lesser degree among females and patients receiving reperfusion therapy.

BACKGROUND AND PURPOSE: Differences in measurement of the extent of acute ischemic stroke using the Alberta Stroke Program Early Computed Tomographic Score (ASPECTS) by non-contrast computed tomography (CT-ASPECTS stratum) and diffusion-weighted imaging (DWI-ASPECTS stratum) may impact the efficacy of endovascular therapy (EVT) in patients with a large ischemic core. METHODS: The RESCUE-Japan LIMIT (Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism Japan-Large IscheMIc core Trial) was a multicenter, open-label, randomized clinical trial that evaluated the efficacy and safety of EVT in patients with ASPECTS of 3-5. CT-ASPECTS was prioritized when both CT-ASPECTS and DWI-ASPECTS were measured. The effects of EVT on the modified Rankin Scale (mRS) score at 90 days were assessed separately for each stratum. RESULTS: Among 183 patients, 112 (EVT group, 53; No-EVT group, 59) were in the CT-ASPECTS stratum and 71 (EVT group, 40; No-EVT group, 31) in the DWI-ASPECTS stratum. The common odds ratio (OR) (95% confidence interval) of the EVT group for one scale shift of the mRS score toward 0 was 1.29 (0.65-2.54) compared to the No-EVT group in CT-ASPECTS stratum, and 6.15 (2.46-16.3) in DWI-ASPECTS stratum with significant interaction between treatment assignment and mode of imaging study (P=0.002). There were significant interactions in the improvement of the National Institutes of Health Stroke Scale score at 48 hours (CT-ASPECTS stratum: OR, 1.95; DWIASPECTS stratum: OR, 14.5; interaction P=0.035) and mortality at 90 days (CT-ASPECTS stratum: OR, 2.07; DWI-ASPECTS stratum: OR, 0.23; interaction P=0.008). CONCLUSION: Patients with ASPECTS of 3-5 on MRI benefitted more from EVT than those with ASPECTS of 3-5 on CT.

Background We aimed to clarify which time-to-maximum of the tissue residue function (Tmax) mismatch ratio is useful in predicting anterior intracranial atherosclerotic stenosis (ICAS)-related large-vessel occlusion (LVO) before endovascular therapy. Methods and Results Patients with ischemic stroke who underwent perfusion-weighted imaging before endovascular therapy for anterior intracranial LVO were divided into those with ICAS-related LVO and those with embolic LVO. Tmax ratios of >10 s/>8 s, >10 s/>6 s, >10 s/>4 s, >8 s/>6 s, >8 s/>4 s, and >6 s/>4 s were considered Tmax mismatch ratios. Binominal logistic regression was used to identify ICAS-related LVO, and the adjusted odds ratio (aOR) and 95% CI for each Tmax mismatch ratio increase of 0.1 were calculated. A similar analysis was performed for ICAS-related LVO with and without embolic sources, using embolic LVO as the reference. Of 213 patients (90 women [42.0%]; median age, 79 years), 39 (18.3%) had ICAS-related LVO. The aOR (95% CI) per 0.1 increase in Tmax mismatch ratio in ICAS-related LVO with embolic LVO as reference was lowest with Tmax mismatch ratio >10 s/>6 s (0.56 [0.43-0.73]). Multinomial logistic regression analysis also showed the lowest aOR (95% CI) per 0.1 increase in Tmax mismatch ratio with Tmax >10 s/>6 s (ICAS-related LVO without embolic source: 0.60 [0.42-0.85]; ICAS-related LVO with embolic source: 0.55 [0.38-0.79]). Conclusions A Tmax mismatch ratio of >10 s/>6 s was the optimal predictor of ICAS-related LVO compared with other Tmax profiles, with or without an embolic source before endovascular therapy. Registration clinicaltrials.gov. Identifier NCT02251665.

Implantable loop recorders (ILRs) are useful for the detection of atrial fibrillation (AF) in patients with cryptogenic stroke (CS). P-wave terminal force in lead V1 (PTFV1) is associated with AF detection; however, data on the association between PTFV1 and AF detection using ILRs in patients with CS are limited. Consecutive patients with CS with implanted ILRs from September 2016 to September 2020 at eight hospitals in Japan were studied. PTFV1 was calculated by 12-lead ECG before ILRs implantation. An abnormal PTFV1 was defined as ≥ 4.0 mV × ms. The AF burden was calculated as a proportion based on the duration of AF to the total monitoring period. The outcomes included AF detection and large AF burden, which was defined as ≥ 0.5% of the overall AF burden. Of 321 patients (median age, 71 years; male, 62%), AF was detected in 106 patients (33%) during the median follow-up period of 636 days (interquartile range [IQR], 436-860 days). The median time from ILRs implantation to AF detection was 73 days (IQR, 14-299 days). An abnormal PTFV1 was independently associated with AF detection (adjusted hazard ratio, 1.71; 95% confidence interval [CI], 1.00-2.90). An abnormal PTFV1 was also independently associated with a large AF burden (adjusted odds ratio, 4.70; 95% CI, 2.50-8.80). In patients with CS with implanted ILRs, an abnormal PTFV1 is associated with both AF detection and a large AF burden.Clinical Trial Registration Information: UMIN Clinical Trials Registry 000044366.

BACKGROUND: The single-device simplicity for mechanical thrombectomy (MT) is now challenged by the complementary efficacy of dual-device first-line with a stent retriever and an aspiration catheter. OBJECTIVE: To compare the outcomes after MT initiated with a single device vs dual devices in acute anterior circulation large vessel occlusion. METHODS: Patients who underwent MT for acute internal carotid artery (ICA) or M1 occlusion between 2015 and 2020 were retrospectively analyzed. We divided patients into 2 groups: single-device first-line, defined as patients who underwent first-device pass with either a stent retriever or aspiration catheter, and dual-device first-line, defined as first-device pass with both devices. RESULTS: One hundred forty-one patients were in the single-device group, and 119 were in the dual-device group. In the dual-device group, coiling or kinking of the extracranial ICA was more frequent ( P = .07) and the guide catheters were less frequently navigated to the ICA ( P < .001). 37% of the single-device group was converted to dual-device use. The proportions of mTICI ≥ 2c after the first pass were similar (33% vs 32%. adjusted odds ratio 0.91, 95% CI 0.51-1.62). An mRS score of 0 to 2 at 3 months was achieved similarly (53% vs 48%, P = .46). The total cost for thrombectomy devices was lower in the single-device group ( P < .001). CONCLUSION: The proportions of first-pass mTICI ≥ 2c were not different between the 2 groups with similar functional outcomes, although the dual-device group more likely to have unfavorable vascular conditions.

BACKGROUND: Anemia can occur due to an aspiration maneuver of blood with thrombi during mechanical thrombectomy (MT) for stroke. However, the association between postoperative anemia and stroke outcomes is unknown. METHODS: In a registry-based hospital cohort, consecutive patients with acute ischemic stroke who underwent MT were retrospectively recruited. Patients were divided into the following three groups according to their hemoglobin (Hb) concentrations within 24 h after MT; no anemia (Hb concentrations ≥13 g/dL for men and ≥ 12 g/dL for women), mild anemia (Hb concentrations of 11-13 g/dL and 10-12 g/dL, respectively), and moderate-to-severe anemia (Hb concentrations <11 g/dL and < 10 g/dL, respectively). A 3-month modified Rankin Scale score of 0-2 indicated a favorable outcome. RESULTS: Of 470 patients, 166 were classified into the no anemia group, 168 into the mild anemia group, and 136 into the moderate-to-severe anemia group. Patients in the moderate-to-severe anemia group were older and more commonly had congestive heart failure than those in the other groups. Patients in the moderate-to-severe anemia group also had more device passes than those in the other groups (p < 0.001). However, no difference was observed in the rate of final extended thrombolysis in cerebral infarction ≥2b reperfusion or intracranial hemorrhage among the groups. A favorable outcome was less frequently achieved in the moderate-to-severe anemia group than in the no anemia group (adjusted odds ratio, 0.46; 95% confidence interval, 0.26-0.81) independent of the baseline Hb concentration. A restricted cubic spline model with three knots showed that the adjusted odds ratio for a favorable outcome was lower in patients with lower Hb concentrations within 24 h after MT. CONCLUSION: Moderate-to-severe anemia within 24 h after MT is independently associated with a reduced likelihood of a favorable outcome. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov, NCT02251665.